Transition-metal-free synthesis of arylboronates via thermal generation of aryl radicals from triarylbismuthines in air

• Yuki Yamamoto,
• Yuki Konakazawa,
• Kohsuke Fujiwara and
• Akiya Ogawa

Beilstein J. Org. Chem. 2024, 20, 2577–2584, doi:10.3762/bjoc.20.216

• the generation of aryl radicals, and the subsequent reaction with bis(pinacolato)diboron afforded a variety of arylboronates in moderate to good yields. Keywords: arylboronates; bis(pinacolato)diboron; radical reactions; transition-metal-free synthesis; triarylbismuthines; Introduction Arylboronates

• are one of the fundamental aryl compounds in organic synthesis, especially in cross-coupling reactions [1][2][3][4][5][6][7][8][9], and their applications are widespread, including dye synthesis, pharmaceutical and agrochemical synthesis, and industrial manufacturing [10][11]. In recent years, a

• variety of transition-metal-catalyzed reactions and photoredox reactions using arylboronates as aryl sources have been energetically investigated for the construction of carbon–carbon or carbon–heteroatom bonds [12][13][14][15]. The preparation of arylboronates often requires pre-functionalized substrates

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• oxidants or reductants, offer unprecedented control of reactions through the continuous variation of the applied potential and the possibility of combination with photochemical processes. This capability is a substantial advantage for performing electrochemical or photoelectrochemical LSF. Ultimately

• electrochemical transformations. Detailed reaction conditions, such as electrolyte, electrode material, and the use of constant current or constant voltage, are presented. Additionally, we discuss the mechanisms of some representative reactions and provide selected examples of LSF of relevant bioactive compounds

• amination: Direct and selective CH-aminations and amidations are challenging reactions. In this context, the regioselective sulfonamidation of (hetero)aromatic groups was achieved by the Lei group via dehydrogenative aryl C–H/N–H cross-coupling [9]. A crucial step in this transformation is the generation of

Visible-light-mediated flow protocol for Achmatowicz rearrangement

• Joachyutharayalu Oja,
• Sanjeev Kumar and
• Srihari Pabbaraja

Beilstein J. Org. Chem. 2024, 20, 2493–2499, doi:10.3762/bjoc.20.213

• developed by Guan-Ben Du et al. [14]. Very often, the photolysis reactions performed in batch process encounter issues that include ineffective illumination, improper mixing, prolonged reaction durations, low quantum efficiency and mass transfer, a limited surface-to-volume ratio, along with an inadequate

• platforms, we herein present a photo-flow platform for Achmatowicz reactions. A novel photo-flow solar panel reactor was fabricated to test and validate the Achmatowicz rearrangement reaction (Figure S1, Supporting Information File 1), and the reaction conditions were optimized with a ruthenium catalyst. As

Machine learning-guided strategies for reaction conditions design and optimization

• Lung-Yi Chen and
• Yi-Pei Li

Beilstein J. Org. Chem. 2024, 20, 2476–2492, doi:10.3762/bjoc.20.212

• /bjoc.20.212 Abstract This review surveys the recent advances and challenges in predicting and optimizing reaction conditions using machine learning techniques. The paper emphasizes the importance of acquiring and processing large and diverse datasets of chemical reactions, and the use of both global

• and local models to guide the design of synthetic processes. Global models exploit the information from comprehensive databases to suggest general reaction conditions for new reactions, while local models fine-tune the specific parameters for a given reaction family to improve yield and selectivity

• scarcity and diversity, as they need to cover a vast reaction space [26][27]. However, collecting data relevant to chemical reactions represents a significant challenge. While specific molecular properties can be precisely computed using existing simulation methods like quantum chemical calculations

HFIP as a versatile solvent in resorcin[n]arene synthesis

• Hormoz Khosravi,
• Valeria Stevens and
• Raúl Hernández Sánchez

Beilstein J. Org. Chem. 2024, 20, 2469–2475, doi:10.3762/bjoc.20.211

• set at 50% probability level. Resorcin[n]arene synthesis. Scope of resorcin[n]arene synthesis using HFIP. aAll reactions were performed with resorcinol (1.0 mmol), aldehyde (1.0 mmol), and HCl (30 mol %) in HFIP (5 mL) at room temperature, and the yields of the reactions are given as isolated yields

• . bGram-scale reaction (1.10 g of resorcinol). cReaction time increased to 24 h. dAll reactions were performed at 50 °C. Optimization of resorcin[n]arene synthesis using HFIP.a Supporting Information Supporting Information File 124: Experimental procedures for reactions, and relevant spectra of all new

Photoredox-catalyzed intramolecular nucleophilic amidation of alkenes with β-lactams

• Valentina Giraldi,
• Giandomenico Magagnano,
• Daria Giacomini,
• Pier Giorgio Cozzi and
• Andrea Gualandi

Beilstein J. Org. Chem. 2024, 20, 2461–2468, doi:10.3762/bjoc.20.210

• reactions limit the utility of this approach. Herein, we report an intramolecular photoredox cyclization of alkenes with β-lactams in the presence of an acridinium photocatalyst. The approach uses an intramolecular nucleophilic addition of the β-lactam nitrogen atom to the radical cation photogenerated in

• intramolecular photoredox reaction. Photoredox-catalyzed intramolecular N-alkylation reactions of various β-lactams. The trans/cis dr was determined by 1H NMR analysis of the crude reaction mixture. Synthesis of the model substrate 14 and its photoredox-catalyzed intramolecular N-alkylation reaction. The trans

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• become increasingly popular in recent years probably due to their useful reactivity, ease of handling, and low toxicity [13]. In particular, hypervalent iodine compounds have been shown to be effective reagents and catalysts for a range of cyclization reactions [14]. In 2015, we reported the iodoarene

• . Optimized structures are shown for the cyclization transition states (hydrogen atoms are omitted for clarity and bond lengths are given in Å). Scope of cyclization reaction. Reactions of di- and trisubstituted alkene substrates. Optimization of cyclization reaction. Supporting Information Supporting

Phenylseleno trifluoromethoxylation of alkenes

• Clément Delobel,
• Armen Panossian,
• Gilles Hanquet,
• Frédéric R. Leroux,
• Fabien Toulgoat and
• Thierry Billard

Beilstein J. Org. Chem. 2024, 20, 2434–2441, doi:10.3762/bjoc.20.207

• not improve the results (Table 1, entry 4). A better yield was obtained by adding first the phenylselenyl chloride and stirring the mixture for 15 min at 0 °C before adding 1a (Table 1, entry 5). During all these reactions the formation of compound 3a was observed as by-product. This compound results

Facile preparation of fluorine-containing 2,3-epoxypropanoates and their epoxy ring-opening reactions with various nucleophiles

• Yutaro Miyashita,
• Sae Someya,
• Tomoko Kawasaki-Takasuka,
• Tomohiro Agou and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2024, 20, 2421–2433, doi:10.3762/bjoc.20.206

• intramolecular interaction between fluorine and metals would also facilitate the smooth progress of these reactions. Such high potential of 1a allowed us to apply it to nucleophilic epoxidation because the resultant epoxyester 2a is recognized as an intriguing building block (Scheme 1). Another expectation to 2a

• shorter period possibly because of its significantly high electrophilicity by the attachment of three strongly electron-withdrawing moieties. Reactions of (E)-3-Rf-2,3-epoxypropanoates 2 with amines, thiols, and metal halides Because the epoxide ring opening is known to occur in an SN2 fashion, compounds

• noticed during the synthesis of 5bc using LiI. Reactions of (E)-4,4,4-trifluoro-2,3-epoxybutanoate 2b with compounds possessing an acidic proton It was very interesting to know that there were scarce examples in the literature [51] on the ring opening of 2,3-epoxyesters in general by the stabilized

Homogeneous continuous flow nitration of O-methylisouronium sulfate and its optimization by kinetic modeling

• Jiapeng Guo,
• Weike Su and
• An Su

Beilstein J. Org. Chem. 2024, 20, 2408–2420, doi:10.3762/bjoc.20.205

• effects of mass and heat transfer. According to the mixing principle, there are active mixers and passive mixers. Passive mixers do not require overly complex equipment and external energy inputs and are extensively used in continuous flow reactions [20][21]. Passive mixers enhance the passive mixing of

• reaction of IO follows first-order kinetics. Given that the reaction order of IO was determined to be 1, Equation 1 was subsequently transformed into Equation 4. As nitration reactions are predominantly second-order, we explored the potential for the reaction order of HNO3 (β) to be either 0 or 1 by

• with increasing H2SO4 mass fraction, which aligns with the findings from previous studies on mixed acid-catalyzed nitration reactions [32][33]. However, the data also reveal a decline in rate constants when the H2SO4 mass fraction exceeds 94%, suggesting a complex interaction at higher acid

Evaluating the halogen bonding strength of a iodoloisoxazolium(III) salt

• Dominik L. Reinhard,
• Anna Schmidt,
• Marc Sons,
• Julian Wolf,
• Elric Engelage and
• Stefan M. Huber

Beilstein J. Org. Chem. 2024, 20, 2401–2407, doi:10.3762/bjoc.20.204

• donors [16][17] from our group as well as of dicationic N-heterocyclic-substituted monodentate catalysts by Nachtsheim [15]. While such compounds are necessary to activate neutral substrates in more challenging reactions, monodentate and monocationic congeners provide sufficient activation in halide

Efficient one-step synthesis of diarylacetic acids by electrochemical direct carboxylation of diarylmethanol compounds in DMSO

• Hisanori Senboku and
• Mizuki Hayama

Beilstein J. Org. Chem. 2024, 20, 2392–2400, doi:10.3762/bjoc.20.203

• were used as received without further purification. Electrochemical reactions were carried out using a constant current power supply (model 5944), Metronix Corp., Tokyo. Diphenylmethanol (1a) [21], bis(4-chlorophenyl)methanol (1b) [22], (2-fluorophenyl)phenylmethanol (1c) [23], (4-methylphenyl

Synthesis, electrochemical properties, and antioxidant activity of sterically hindered catechols with 1,3,4-oxadiazole, 1,2,4-triazole, thiazole or pyridine fragments

• Daria A. Burmistrova,
• Andrey Galustyan,
• Nadezhda P. Pomortseva,
• Kristina D. Pashaeva,
• Maxim V. Arsenyev,
• Oleg P. Demidov,
• Mikhail A. Kiskin,
• Andrey I. Poddel’sky,
• Nadezhda T. Berberova and
• Ivan V. Smolyaninov

Beilstein J. Org. Chem. 2024, 20, 2378–2391, doi:10.3762/bjoc.20.202

• corresponding thiols. The starting reagents such as substituted 1,3,4-oxadiazole-2-thiols and 4H-triazole-3-thiols are characterized by thiol–thione tautomerism, therefore their reactions with 3,5-di-tert-butyl-6-methoxymethylcatechol can proceed at the sulfur or nitrogen atom. In the case of mercapto

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• were achieved exclusively (dr > 20:1) in good yields (83% and 89%) and enantioselectivity (96% and 90%). On the other hand, the reactions with (Z)-crotyldioxaborinane 30 resulted in lower yields (33% for 32 and 61% for 34). However, the diastereoselectivity towards the syn products remained notably

• for the resolution of chiral amines [28]. However, it was not until 2004 that they were recognised as efficient chiral Brønsted acid organocatalysts for asymmetric Mannich reactions [29]. Malkov and co-workers revealed [30] that (R)-TRIP can act as a very efficient catalyst for the kinetic resolution

• method involves squaramide 51-catalysed chloride abstraction from readily accessible N-carbamoyl α-chloroglycinates 48 or 54 (Scheme 11) [35], with a simultaneous nucleophilic attack of allylsilane 49 (Scheme 11A) or allylstannane 55 (Scheme 11B). The reactions are highly sensitive to moisture and oxygen

Tandem diazotization/cyclization approach for the synthesis of a fused 1,2,3-triazinone-furazan/furoxan heterocyclic system

• Yuri A. Sidunets,
• Valeriya G. Melekhina and
• Leonid L. Fershtat

Beilstein J. Org. Chem. 2024, 20, 2342–2348, doi:10.3762/bjoc.20.200

• Federation 10.3762/bjoc.20.200 Abstract A straightforward protocol for the synthesis of a previously unknown [1,2,5]oxadiazolo[3,4-d][1,2,3]triazin-7(6H)-one heterocyclic system was developed. The described approach is based on tandem diazotization/azo coupling reactions of (1,2,5-oxadiazolyl)carboxamide

• a 1,2,3-triazin-4-one core. The proposed method is based on tandem diazotization/azo coupling reactions of the corresponding amides (Scheme 1). In addition, application perspectives of thus prepared heterocyclic entities as thermally stable components of functional organic materials or NO-donor drug

• coupling reactions of the obtained compounds 2. It should be emphasized that amino-1,2,5-oxadiazoles correspond to very weak nucleophiles due to the highly electron-withdrawing effect of the heterocycle. Our previous efforts achieved a certain result indicating that (1,2,5-oxadiazolyl)diazonium salts

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• chemical proteomics workflow visualizing the main steps; cells incubation with the probe, bioorthogonal reaction between probe–protein conjugates and a tag followed by analysis of those labeled proteins. Products of the CuAAC side reactions. Search possibilities on peptide-level characterization. A

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• . Mild enolization of thioesters allows for the generation of Michael adducts with good yields and stereoselectivities. Reactions in a ball mill afford product formation with similar efficacy to solution-phase reactions but with slightly reduced enantioselectivity, yet they yield products in just one

• hour compared to 24 or even 168 hours in solution-based reactions. It is noteworthy that this represents one of the early reports on the application of iminium catalysis using first-generation chiral amines under mechanochemical conditions, along with the utilization of easily enolizable thioesters as

• studies by Bolm [12][13], and Juaristi et al. [14]. have significantly advanced chiral secondary amine-catalyzed stereoselective reactions under ball milling conditions, representing a widely explored activation mode in mechanochemical-mediated transformations. However, reports on chiral primary iminium

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• available in the absence of Lewis acid activation (Scheme 1a) [11][12]. A variety of Lewis acid activators have been reported [13][14][15][16][17][18][19][20][21][22] in an array of group-transfer reactions, including trifluoromethylation, cyanation, and fluorination. Brønsted acid activation has also been

• center [26][27]. Despite the prevalence of acid-activation in promoting carbon [28], oxygen [29][30], sulfur [31], chlorine [32], and fluorine [33] transfer reactions of hypervalent iodine compounds, these strategies have not been applied to activation of iminoiodinanes for nitrene transfer chemistry. We

• ). Increasing the reaction temperature negatively affected the efficiency of aziridination: Reactions performed at 30 or 50 °C afforded 3a in 50% and 43% yield, respectively (Table 1, entries 5 and 6). Replacing HFIP with 2,2,2-trifluoroethanol (TFE), which is also a commonly encountered fluorinated alcohol

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• Research (NCCR) Catalysis, ETH Zurich, Zurich CH-8093, Switzerland 10.3762/bjoc.20.196 Abstract Organocatalysis has established itself as a third pillar of homogeneous catalysis, besides transition metal catalysis and biocatalysis, as its use for enantioselective reactions has gathered significant

• ]. Despite the prominence of organocatalytic reactions, catalyst development has so far mostly been conducted guided by intuition of skilled organic chemists. Given that organocatalytic reactions are governed by different competing interactions, the influence of a change in molecular structure is often non

• physicochemical descriptors. A prominent early example are Hammett parameters, developed in 1937 [26][27], that relate substituent parameters to the equilibrium constant of the deprotonation of a substituted benzoic acid. The derived substituent parameters are used to gain insight into the mechanism of reactions

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• [D2]-isonitriles across 8 multicomponent reactions (MCRs) to give diverse arrays of deuterated products. A highlight is the synthesis of several FDA-approved calcium channel blockers, selectively deuterated at a t1/2 limiting metabolic soft-spot via use of [D1]-aldehydes. Surrogate pharmacokinetic

• significantly enhanced metabolic stability, a key parameter for property-based design efforts. Keywords: deuterated aldehydes; deuterated formamides; deuterated isocyanides; DHPs; kinetic isotope effect; Leuckart–Wallach; microsomal stability; multicomponent reactions; Introduction Multicomponent reactions

• (MCRs) are one-pot reactions that utilize three or more readily available starting materials [1][2][3][4]. Typically, MCRs use reactive functional groups such as ketones or aldehydes, carboxylic acids, amines, and isocyanides where these simple building blocks can be utilized to form large libraries of

gem-Difluorination of carbon–carbon triple bonds using Brønsted acid/Bu₄NBF₄ or electrogenerated acid

• Mizuki Yamaguchi,
• Hiroki Shimao,
• Kengo Hamasaki,
• Keiji Nishiwaki,
• Shigenori Kashimura and
• Kouichi Matsumoto

Beilstein J. Org. Chem. 2024, 20, 2261–2269, doi:10.3762/bjoc.20.194

• the use of HF or its complexes as a reagent. These reactions seem to proceed via the formation of the vinyl fluoride as the intermediate [25][26][27][28]. In the first example, Olah and co-workers reported the reaction of terminal alkynes with HF/pyridine (Olah reagent) (Figure 1, reaction 1) [29][30

• solution of Bu4NBF4/CH2Cl2 containing substrates might also promote the same reactions (Figure 1, reaction 6, electrochemical method). Currently, electrochemistry can be regarded as a promising technique in organic synthesis, because heavy-metal reagents can be avoided for the oxidation or reduction of

• , entry 6), but TfOH gave the product 2a in 72% yield (Table 1, entry 7). As for the solvent, CH3CN slightly afforded 2a, although N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) were not suitable for the reactions (Table 1, entries 8–10). A fluorine source, such as Bu4NF or BF3·Et2O, instead of

Cell-free protein synthesis with technical additives – expanding the parameter space of in vitro gene expression

• Tabea Bartsch,
• Stephan Lütz and
• Katrin Rosenthal

Beilstein J. Org. Chem. 2024, 20, 2242–2253, doi:10.3762/bjoc.20.192

• ions in CFPS reactions to which choline chloride was added ranged from 232 to 602 mM, exceeding the cytoplasmic inorganic ion concentration of 300 mM. Osmolarity is also increased by increasing salt concentrations as well. With the addition of 10% choline chloride/urea, the osmolarity of the CFPS

• a known mechanism that positively influences CFPS reactions [25]. Interestingly, increasing the concentration of PEG-8000, and thus increasing the viscosity and macromolecular concentration of the CFPS solution towards the properties of the cytoplasm, has a negative effect on the sfGFP synthesis

• from the 100% of pure water, additives decreased that value by the percentage of their contribution. Calculations and further details can be found in Supporting Information File 1. Cell-free protein synthesis The CFPS system was prepared and the reactions performed according to Rolf et al. [18] with

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• azide–alkyne cycloaddition; Introduction The strain-promoted azide–alkyne cycloaddition (SpAAC) is one of the most representative metal-free click chemistry reactions [1][2][3][4][5]. SpAAC has been mainly employed in bioconjugation in the fields of chemical biology and medicinal chemistry due to its

• oxidation-controlled cyclooctyne-1,2-quinone cycloaddition (SPOCQ) was developed and employed in the same fields of chemical biology [6][7]. On the other hand, the use of the SpAAC in materials science was slow. We developed another class of metal-free click chemistry reactions, such as the [2 + 2

• ] cycloaddition–retroelectrocyclization (CA-RE) between electron-rich alkynes and electron-deficient olefins [8]. The [2 + 2] CA-RE click reactions were employed to produce a variety of functional materials, such as nonlinear optical chromophores [9][10], super acceptors [11][12], ion sensing D–A systems [13

Selective hydrolysis of α-oxo ketene N,S-acetals in water: switchable aqueous synthesis of β-keto thioesters and β-keto amides

• Haifeng Yu,
• Wanting Zhang,
• Xuejing Cui,
• Zida Liu,
• Xifu Zhang and
• Xiaobo Zhao

Beilstein J. Org. Chem. 2024, 20, 2225–2233, doi:10.3762/bjoc.20.190

• thioesters and β-keto amides is reported. In refluxing water, the hydrolysis reactions of α-oxo ketene N,S-acetals in the presence of 1.0 equiv of dodecylbenzenesulfonic acid effectively afforded β-keto thioesters in excellent yield, while β-keto amides were successfully obtained in excellent yield when the

• hydrolysis reactions were carried out in the presence of 3.0 equiv of NaOH. The green approach to β-keto thioesters and β-keto amides avoids the use of harmful organic solvents, thiols and thiolacetates as well as amines, which could result in serious environmental and safety issues. Keywords: α-oxo ketene

• thioesters and acyl chlorides (Scheme 1a, path 7) [30]. For β-keto amides, they could be efficiently synthesized from the nucleophilic substitution reactions of amines with β-keto acids (Scheme 1b, path 1) [31][32][33], β-keto esters (Scheme 1b, path 2) [34] and the nucleophilic addition reactions of amines

Electrochemical allylations in a deep eutectic solvent

• Sophia Taylor and
• Scott T. Handy

Beilstein J. Org. Chem. 2024, 20, 2217–2224, doi:10.3762/bjoc.20.189

• 1:3 molar ratio of tetrabutylammonium bromide and ethylene glycol (TBAB/EG) [28]. Using the reaction of p-anisaldehyde with allyl bromide as a test case, reactions were performed using three sets of different sacrificial electrodes as well as non-sacrificial graphite. As can be seen in Table 1, tin

• starting material were recovered via extraction with methoxycyclopentane and the CC/EG used in another cycle. Through two recyclings, the reactions were similar in efficiency, although the DES became increasingly viscous as the tin byproducts built up and it became impractical to recycle the DES further

• flash column chromatography. In between reactions, the tin electrodes were rinsed with DI water and acetone, then polished using diamond polish. This helped prevent buildup on the electrode surfaces. General C/C procedure with TBAB/EG To a 10 mL ElectraSyn 2.0 vial containing a magnetic stir bar were